Variant rs587779351 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1PM2PP3_StrongPP5

The NM_003401.5(XRCC4):c.127T>A(p.Trp43Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

XRCC4
NM_003401.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.19

Variant links:

Genes affected

XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

XRCC4 links:

XRCC4 (HGNC:):

XRCC4 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_003401.5 (XRCC4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 5-83105046-T-A is Pathogenic according to our data. Variant chr5-83105046-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1329084.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC4	NM_003401.5 linkuse as main transcript	c.127T>A	p.Trp43Arg	missense_variant	2/8	ENST00000396027.9	NP_003392.1	Q13426-2A0A024RAL0Q7Z763

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9 linkuse as main transcript	c.127T>A	p.Trp43Arg	missense_variant	2/8	5	NM_003401.5	ENSP00000379344.4		Q13426-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460594

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726576

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Short stature, microcephaly, and endocrine dysfunction

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T;.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;.;.;T

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.8

M;M;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-11

D;D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.99

MutPred

0.89

Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);Gain of disorder (P = 0.0068);

MVP

0.86

MPC

0.24

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over